Titanium tetrafluoride catalysis for the dehydrative conversion of diphenylmethanols to symmetric and unsymmetric ethers

In contrast to the conversion of diphenylmethanol to the corresponding halides with an equivalent of titanium tetrachloride or -bromide, catalytic (50 mol%) titanium tetrafluoride converts benzhydrols in diethyl ether or dichloromethane to bis(benzhydryl) ethers within 0.5–1 h at room temperature. Cross ether formation with diphenylmethanols and primary aryl or aliphatic alcohols is achieved in the presence of 25 mol% TiF4 in refluxing toluene as solvent. A tentative mechanism involving a carbocation intermediate has been proposed.


Introduction
The formation of diphenylmethyl ethers (DPME) from alcohols and their trans-etherication have been subjects of investigation for several decades due to the interest in DPME protection of alcohols during multi-step organic syntheses. 1In addition, DPMEs are an integral part of several pharmacologically important molecules, such as the antihistamine diphenhydramine (benzhydryl dimethylaminoethyl ether) hydrochloride (Benadryl ® ), 2 anti-cholinergic orphenadrine hydrochloride (Disipal ® ), 3 anti-depressant tofenacin hydrochloride (Elamol ® ), 3 etc.(Fig. 1).Several procedures for the direct self-and cross-etherication of benzyl alcohols, particularly diphenylmethanol have been reported in the literature. 4,5The preparation of DPMEs reported eight decades ago used tridiphenylmethylphosphate as an alkylating agent, accelerated using triuoracetic acid as a catalyst. 6Bis(diphenylmethyl) ether was also prepared using (diethylamino)sulfur triuoride (DAST), 7 zeolite, 8 or p-toluenesulfonyl chloride (p-TsCl), 9 etc. as catalysts.Cross ethers from DPM and alcohols can be prepared employing several catalysts, such as Fe(NO 3 )  22 and FeCl 3 23 have also been reported.Our accidental discovery of the etherication of diphenylmethanols in the presence of titanium tetrauoride (TiF 4 ) originated from the reduction of benzophenone to diphenylmethanol (DPM, 1a) with borane-ammonia in the presence of titanium tetrachloride (TiCl 4 ). 24We had observed that in addition to DPM, the corresponding diphenylmethyl chloride could also be prepared by altering the stoichiometry of TiCl 4 . 25his led to a titanium tetrachloride or -bromide-mediated conversion of benzhydrols to benzydryl halides (Scheme 1), 25 which serve as precursors for several piperazine derivatives possessing biological properties. 26This dehydroxyhalogenation was extended to benzyl alcohol and other alcohols as well. 25We had postulated that the halogenation of DPM and alcohols proceeds via a carbocation intermediate and, indeed, recently reported on the use of benzyl alcohols as pre-electrophiles for

PAPER
Friedel-Cras reactions in the presence of TiCl 4 . 27Based on a reported titanium tetrauoride-mediated uorination during Prins cyclization, 28 we were interested in examining the potential for a dehydroxyuorination of alcohols using TiF 4 .Unexpectedly, the reaction of DPM with a molar equiv. of TiF 4 in diethyl ether (Et 2 O) at room temperature (RT) resulted in the formation of the corresponding bis(benzhydryl) ether (2a) in 91% yield within 30 minutes.Further examination of this reaction has led to an efficient dehydrative dimerization of substituted DPMs and cross-etherication with primary alcohols.An examination of the plausible mechanism of this reaction was also undertaken.

Results and discussion
The effect of stoichiometry, solvent, concentration, etc. on the TiF 4 -mediated room-temperature self-etherication was assessed rst (Table 1).Optimization of the catalyst stoichiometry revealed that 50 mol% of TiF 4 is sufficient to complete the dehydrative dimerization.The reaction was very facile at RT in Et 2 O, dichloromethane (DCM), and hexanes.A reaction in toluene at RT gave the bis(diphenylmethyl) ether 2a and the Friedel-Cras product 5 in an 84 : 16 ratio (vide infra).The reaction in other solvents, such as tetrahydrofuran (THF), and nitromethane show product formation, but fail to undergo completion (TLC).Solvents such as dimethoxyethane (DME) and acetonitrile do not facilitate self-etherication, probably due to complexation with the catalyst. 29The solubility of the catalyst in the solvents was not favourable for a higher concentration reaction and optimal yields were achieved in 0.33 M Et 2 O, DCM, and n-hexane.The best yields were obtained when using DCM as solvent.
Having standardized the reaction, a series of diphenylmethanols, prepared via the sodium borohydride reduction of the corresponding benzophenones or Grignard reaction of the corresponding benzaldehydes bearing an electron-donating and -with-drawing substituent on the phenyl ring, were converted to the corresponding bis(benzydryl) ethers in Et 2 O or CH 2 Cl 2 .Thus, DPMs with a 4-bromo-(1b), 4-methoxy-(1c), 4methyl-(1d), 4-nitro-(1e), and 4-uoro-(1f) substituent on one of the phenyl rings were converted to the bis-ethers 2b-2f in 92-99% yields (Table 2).DPMs substituted with electronwithdrawing groups and halogens provided the corresponding bis-ethers in near quantitative yields.However, those with electron-donating groups provided slightly lower yields.Evidently, this may be attributed to the stability of the intermediate carbocations (vide infra).
Curious whether benzyl alcohol (3a) can be converted to dibenzyl ether in the presence of TiF 4 , a reaction was performed in Et 2 O at RT. Unlike the reaction of 3a with titanium tetrachloride and -bromide which led to the corresponding benzyl halides, 25 the reaction with TiF 4 did not yield any of the uoride nor the corresponding dibenzyl ether products; the alcohol was recovered completely.
We sought to exploit this lack of reactivity of a primary alcohol to develop a direct cross-etherication/protection of alcohols by preparing the DPM ether via TiF 4 catalysis.Unfortunately, a reaction of 1a and 3a in diethyl ether in the presence of 50 mol%, or even 100 mol% TiF 4 resulted only in the formation of 2a and none of the cross ether (4aa).Fortuitously, when the above reaction was performed in the presence of 25 mol% TiF 4 at higher temperature, in reuxing toluene, 4aa was isolated in 91% yield within 2 h.Notably, not even traces of 2a were observed during this reaction.To verify whether the formation of 4aa is proceeding via a trans-etherication of 2a, 11 a solution of 2a and 3a in toluene was reuxed for 2 h, with and without TiF 4 .None of 4aa was formed in the latter reaction, but the former reaction revealed the formation of 4aa, albeit at a slow rate.The reversibility of the bis-ether formation step is  discussed later (vide infra: mechanism).A similar reaction with methanol (3b) in reuxing toluene provided 96% of the cross ether (4ab) and none of the dimer 2a (Table 3).Ethanol (3c), and n-butanol (3d) provided the corresponding ethers 4ac and 4ad, in 91% and 96% yields, respectively.Similarly, 4-bromo-substituted benzhydrol (1b) provided the corresponding methoxy ether (4bb) in 99% yield.2-Chloroethanol (3e) and p-chlorobenzyl alcohol (3f) were also treated with 1a, which provided high yields of 91% and 98% respectively for the corresponding DPM ethers, 4ae and 4af, respectively.Chloroether 4ae is an intermediate for the preparation of Benadryl ® . 2 More hindered 2°-and 3°-alcohols, cyclohexanol (3g) and tertbutanol (3h), respectively failed to provide the desired ether-ication products 4ag and 4ah respectively in toluene as solvent, but 2a was formed.On the other hand, allyl alcohol (3i) when reacted with the DPMs 1a and 1b yielded 94% and 97% of ethers 4ai and 4bi, respectively.

Reaction mechanism
Having developed efficient protocols for the preparation of symmetrical and unsymmetrical ethers from DPMs, we turned our attention to rationalize the difference in behaviour of the tetrauoro-reagent compared to the tetrachloro-and tetrabromotitanium derivatives.We had earlier established that the chlorination and bromination occurs via a carbocation, 25 which was conrmed by carrying out a Friedel-Cras reaction with pro-electrophiles, such as alcohols in the presence of the latter reagents. 27It is known that alcohols and amines form a complex with titanium tetrauoride. 29Once this occurs, an S N 1 pathway can be envisaged for the formation of the ether involving an intermediate carbocation (Scheme 2).
The intermediacy of the carbocation can be presumed from the Friedel-Cras alkylation product during the reaction of 1a in toluene as solvent at RT (Table 1, entry 6).Indeed, to demonstrate the presence of the carbocation unambiguously, a Friedel-Cras reaction of DPM and an equivalent of TiF 4 was conducted in reuxing benzene, anticipating the formation of triphenylmethane (5).The reaction proceeded to completion in 2 h and the 1 H NMR of the product revealed the formation of 5 along with 2a in a 2 : 1 ratio.To facilitate the Friedel-Cras alkylation, we carried out a similar reaction with DPM and 50 mol% TiF 4 in reuxing toluene, which is a better substrate for Friedel-Cras due to the increased electron density of the phenyl ring.Indeed, we isolated (p-tolylmethylene)dibenzene   (5) exclusively in 96% yield, conrming the presence of a carbocation intermediate (Table 4).It is noteworthy that the triphenylmethane moiety forms the backbone for several dyes, 30,31 and drugs possessing antiseptic, 32 antihelmintic, and antimicrobial properties. 33They are also present in photodynamic therapy 34 agents.

Conclusion
In conclusion, we have developed a facile titanium tetrauoridecatalysed dehydration protocol for the synthesis of symmetric and unsymmetric ethers from diphenylmethanol and related compounds by themselves at RT or with primary alcohols in reuxing toluene.This quick, room temperature synthesis of symmetrical ethers affords yields in the range of 92-99% and the cross-ethers in reuxing toluene in 91-99% yields.Mechanistic studies point to a carbocation pathway, which is conrmed by a TiF 4 -mediated Friedel-Cras reaction.Although the process is efficient in preparing ethers, it fails when amines are used as the nucleophile, perhaps due to the complexation of TiF 4 with amines.Continued studies on a potential dehydrative amination are underway.

Table 1
Optimization of reaction conditions for the preparation of 2a from 1a in the presence of catalytic TiF 4 at RT a Entry TiF 4 , mol% Solvent Reaction time, h b Product 1a : 2a (yield%) a All reactions were carried out at 1 mmol scale with 0.33 M solvent.b Isolated yields.c Friedel-Cras reaction product.

Table 2
Preparation of bis(diphenylmethyl) ethers in the presence of catalytic TiF 4 at room temperature a a Reaction at 1 mmol scale with 0.33 M Et 2 O/CH 2 Cl 2 at RT in the presence of 50 mol% TiF 4 .b Isolated yields.

Table 3
Preparation of alkyl (diphenylmethyl) ethers in the presence of catalytic TiF 4

Table 4
TiF 4 -catalyzed Friedel-Crafts reaction a a Reactions carried out at 1 mmol scale.